1.NAME OF THE MEDICINAL PRODUCT
Ketorolac Tromethamine Opthalmic Solution USP 0.5% w/v Taj Pharma.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each ml contains:

Active: Ketorolac Tromethamine USP 0.5%w/v
Preservative: Benzalkonium chloride 0.01%

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM
Eye drops, solution.
Clear, colourless to pale yellow aqueous solution.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications
Ketorolac is indicated for the prophylaxis and reduction of inflammation and associated symptoms following ocular surgery.

Ketorolac is indicated in adults.

4.2  Posology and method of administration
Posology
Post-operative inflammation:

One drop instilled into the eye three times daily starting 24 hours pre-operatively and continuing for up to three weeks post-operatively.

Paediatric population
There is no relevant use of Ketorolac in the paediatric population in the indication: For the prophylaxis and reduction of inflammation following cataract surgery.

Method of administration
Ocular use.

Instil one drop of the solution into the inferior conjunctival sac of the eye to be treated, while pulling the lower eyelid gently downwards and looking upwards.

If Ketorolac is used concomitantly with other topical eye medications there must be an interval of at least 5 minutes between the two medications.

4.3 Contraindications
Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1.

The potential exists for cross-sensitivity to acetylsalicylic acid and other non-steroidal anti-inflammatory drugs. Ketorolac is contraindicated in individuals who have previously exhibited sensitivities to these drugs.

4.4 Special Warnings and precautions for use
It is recommended that Ketorolac be used with caution in patients with known bleeding tendencies or who are receiving other medications which may prolong bleeding time.

In common with other anti-inflammatory drugs, Ketorolac may mask the usual signs of infection.

All non-steroidal anti-inflammatory drugs (NSAIDs) may slow down or delay wound healing. Concomitant use of NSAIDs and topical steroids can increase the potential for healing problems.

Concomitant use of Ketorolac and topical corticosteroids should be exercised with caution in patients susceptible to corneal epithelial breakdown.

Use of topical NSAIDS may result in keratitis. In some patients, continued use of topical NSAIDs may result in epithelial breakdown, corneal thinning, corneal erosion, corneal ulceration or corneal perforation. These events may be sight threatening. Patients with evidence of corneal epithelial breakdown should immediately discontinue use of topical NSAIDs and should be closely monitored for corneal health.

Topical NSAIDs should be used with caution in patients with complicated ocular surgeries, corneal denervation, corneal epithelial defects, diabetes mellitus, ocular surface diseases (e.g. dry eye syndrome), rheumatoid arthritis, or repeat ocular surgeries within a short period of time, as they may be at increased risk for corneal adverse events which may become sight threatening.

Post marketing experience with topical NSAIDs also suggest that use more than 24 hours prior to surgery or use beyond 14 days post surgery may increase patient risk for the occurrence and severity of corneal adverse events.

The preservative in Ketorolac, benzalkonium chloride, may cause eye irritation. Contact lenses must be removed prior to application, with at least a 15-minute wait before reinsertion. Benzalkonium chloride is known to discolour soft contact lenses. Contact with soft contact lenses must be avoided.

There have been post-marketing reports of bronchospasm or exacerbation of asthma in patients, who have either a known hypersensitivity to aspirin/non-steroidal anti-inflammatory drugs or a past medical history of asthma associated with the use of Ketorolac, which may be contributory. Caution is recommended in the use of Ketorolac in these individuals (see section 4.8).

Patients should be instructed to avoid allowing the tip of the dispensing container to contact the eye or surrounding structures to avoid injury and contamination of eye drops.

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms.

4.5 Interaction with other medicinal products and other forms of interaction
No interaction studies have been performed.

Ketorolac has been safely administered with systemic and ophthalmic medications such as antibiotics, sedatives, beta blockers, carbonic anhydrase inhibitors, miotics, mydriatics, local anaesthetics and cycloplegics.

Ketorolac may slow or delay healing. Topical corticosteroids are also known to slow or delay healing. Concomitant use of topical NSAIDs and topical corticosteroids may increase the potential for healing problems (see section 4.4).

4.6 Fertility, Pregnancy and lactation
Pregnancy
There are no adequate data from the use of eye drops containing ketorolac in pregnant women. Studies in animals have shown reproductive toxicity. Inhibition of prostaglandin synthesis may negatively affect pregnancy and/or embryonal/foetal development and/ or postnatal development. Although a very low systemic exposure is expected after the use of ketorolac eye drops, Ketorolac is not recommended during pregnancy.

Breast-feeding
Ketorolac should not be used during breast-feeding. Ketorolac is excreted in human milk after systemic administration.

Fertility
There are no adequate data from the use of ketorolac on fertility in humans.

4.7 Effects on ability to drive and use machines
Transient blurring of vision may occur on instillation of eye drops. Do not drive or use hazardous machinery unless vision is clear.

4.8 Undesirable Effects
The most frequent adverse events reported with the use of Ketorolac are transient stinging and burning on instillation.

The frequency of adverse reactions documented during clinical trials of ketorolac and through post-marketing experience is given below and is defined as follows:

Very Common (≥ 1/10);
Common (≥1/100 to <1/10);
Uncommon (≥1/1,000 to <1/100);
Rare (≥1/10,000 to <1/1,000);
Very Rare (<1/10,000);
Not Known (cannot be estimated from available data).

Immune system disorders
Common: Hypersensitivity including localised allergic reactions
Nervous system disorders
Common: Headache
Eye Disorders
Very Common: Eye irritation (including burning sensation)

Eye pain (including stinging)

Common: Superficial (punctate) keratitis

Eye and/or eyelid oedema

Ocular pruritus

Conjunctival hyperaemia

Eye infection

Eye inflammation

Iritis

Keratic precipitates

Retinal haemorrhage

Cystoid mketorolac oedema

Eye trauma

Increased intraocular pressure

Blurred and/or diminished vision

Uncommon: Corneal ulcer

Corneal infiltrates

Eye dryness

Epiphora

Not known: Corneal damage, e.g. thinning, erosion, epithelial breakdown and perforation*

ulcerative keratitis

eye swelling

ocular hyperaemia

Respiratory, thoracic and mediastinal disorders
Not known: Bronchospasm or exacerbation of asthma**

*Occasional post marketing reports of corneal damage including corneal thinning, corneal erosion, epithelial breakdown and corneal perforation have been received. These occurred mainly in patients using concomitant topical corticosteroids and/or with predisposing co-morbidity (see section 4.4).

**There have been post-marketing reports of bronchospasm or exacerbation of asthma, in patients, who have either a known hypersensitivity to aspirin/non-steroidal anti-inflammatory drugs or a past medical history of asthma, associated with the use of Ketorolac which may be contributory.

None of the typical adverse reactions reported with the systemic non-steroidal anti-inflammatory agents (including ketorolac) have been observed at the doses used in topical ophthalmic therapy.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

4.9 Overdose
No case of overdose has been reported. Overdose is unlikely to occur via the recommended method of administration.

If accidentally ingested, drink fluids to dilute.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Anti-inflammatory agents, non-steroids

Ketorolac (ketorolac) is a non-steroidal anti-inflammatory agent demonstrating analgesic and anti-inflammatory activity. Ketorolac inhibits the cyclo-oxygenase enzyme essential for biosynthesis of prostaglandins. Ketorolac has been shown to reduce prostaglandin levels in the aqueous humour after topical ophthalmic administration.

Ketorolac given systemically does not cause pupil constriction. Results from clinical studies indicate that Ketorolac has no significant effect on intra-ocular pressure.

 5.2 Pharmacokinetic properties
a) General characteristics

Absorption

Rabbit aqueous humor bioavailability:
Mean concentration of total radioactivity 0.856 µg-equiv./ml @ 0.5 hr
1.607 µg-equiv./ml @ 2 hr
Tmax 3.38 hr
Cmax 1.905 µg-equiv./ml
AUC (0-8 hr) 9.39 µg-equiv. hr/ml
Total AUC 13.53 µg-equiv. hr/ml
Half-life 3.77 hr
Absolute ocular bioavailability 3.7%

After topical ocular doses in the rabbit the half life of total radioactivity in aqueous humor was longer than after intracameral injection. This suggests that topical dosing may lead to a “reservoir” effect in the corneal epithelium and continued flux of drug from the reservoir into the aqueous humor.

Distribution

After ophthalmic doses were administered to rabbits, peak concentrations of radioactivity were achieved within 1 hour in the ocular tissues and were highest in the cornea (6.06 mcg-eq/ml). At 1 hour, the majority of the radioactivity (0.9% of administered dose) was recovered from the sclera (0.58%) and cornea (0.24%), and smaller amounts were recovered from the aqueous humor (0.026%), vitreous humor (0.023%), retina-choroid (0.018%), iris-ciliary body (0.007%) and lens (0.002%).

Relative to plasma AUC values, the AUC’s in rabbits were higher for cornea (104 fold), sclera (27 fold), iris-ciliary body (5.8 fold), retina-choroid (5.6 fold), aqueous humor (3.3 fold) and approximately one-half in the vitreous humor and lens. After ophthalmic administration, concentrations of drug-related radioactivity were higher in the ocular tissues and lower in plasma compared with those after IV dosing.

Systemic Absorption

After ophthalmic doses in the rabbit, ketorolac was absorbed rapidly into the systemic circulation (Tmax, 15 min). Plasma half-lives after ophthalmic doses (6.6 – 6.9 hr) were longer than those after IV administration (1.1 hr), suggesting that removal of drug from eye into the venous circulation may be rate-limiting. By comparison of drug levels in aqueous humor after intracameral injection vs. plasma levels after IV administration, ketorolac was shown to clear more rapidly from plasma (6 ml/min) than from the anterior chamber (11 mcl/min).

In the cynomolgus monkey, peak plasma levels of ketorolac occurred at 1.1 hr after the ophthalmic dose. The plasma half-life of ketorolac was similar after ophthalmic (1.8 hr) and IV doses (1.6 hr).

The majority of the ophthalmic dose was excreted in urine (66% in rabbit and 75% in monkey) and a small amount in faeces (11% in rabbit and 2% in monkey). The extent of systemic absorption after ophthalmic dosing averaged 73% in the rabbit and 76% in the cynomolgus monkey.

Metabolism

After ophthalmic administration in rabbits, ketorolac represented the major component (more than 90%) of radioactivity in aqueous humor and plasma and the p-hydroxy metabolite accounted for 5% of radioactivity in plasma. Ketorolac was also the major component (96%) of plasma radioactivity after ophthalmic dosing in monkeys.

After ophthalmic dosing in the rabbit, 72%, 17% and 6% of the total radioactivity in urine was comprised of intact ketorolac, p-hydroxy ketorolac and other polar metabolites, respectively. After IV dosing, the relative proportions of total radioactivity in urine averaged 6% as intact ketorolac, 68% as p-hydroxy ketorolac and 22% as polar metabolites.

In the monkey, intact ketorolac and its polar metabolite accounted for 32% and 65% of the total radioactivity in urine, respectively, after ophthalmic dosing, and 50% and 49% of the radioactivity in urine, respectively, after IV dosing. Thus, the metabolism of ketorolac was qualitatively similar after ophthalmic and IV administration in the monkey and rabbit.

b) Characteristics in patients

Ketorolac tromethamine solutions (0.1% or 0.5%) or vehicle were instilled into the eyes of patients approximately 12 hours and 1 hour prior to surgery. Concentrations of ketorolac in aqueous humor sampled at the time of surgery were at the lower limit of detection (40 ng/ml) in 1 patient and below the quantitation limit in 7 patients dosed with 0.1% ketorolac tromethamine. The average aqueous humor level of ketorolac in patients treated with 0.5% ketorolac tromethamine was 95 ng/ml. Concentrations of PGE2 in aqueous humor were 80 pg/ml, 40 pg/ml and 28 pg/ml in patients treated with vehicle, 0.1% ketorolac tromethamine and 0.5% ketorolac tromethamine, respectively.

In the 21-day multiple dose (TID) tolerance study in healthy subjects, only 1 of 13 subjects had a detectable plasma level pre-dose (0.021 μg/ml). In another group of 13 subjects, only 4 subjects showed very low plasma levels of ketorolac (0.011 to 0.023 μg/ml) 15 minutes after the ocular dose.

Thus, higher levels of ketorolac in the aqueous humor and very low or no detectable plasma levels after ophthalmic doses, suggest that the use of ketorolac tromethamine by the ophthalmic route in treatment of ocular disorders results in quite low systemic absorption in patients.

5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development.

Acute, sub-acute and chronic studies of Ketorolac in experimental animals have established the safety of the drug. In addition, octoxinol 40 was separately evaluated for its ocular safety. Ketorolac was found to be non-irritating, it did not demonstrate a local anaesthetic effect, it did not influence the healing of experimental corneal wounds in rabbits, it did not enhance the spread of experimental ocular infections of Candida albicansHerpes simplex virus type one, or Pseudomonas aeruginosa in rabbits, and it did not increase the ocular pressure of normal rabbit eyes.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients
Sodium chloride
Benzalkonium chloride
Disodium edentate
Octoxinol 40
1N Sodium hydroxide or 1N Hydrochloric acid, to adjust pH
Purified water

6.2 Incompatibilities
Not applicable.

6.3  Shelf life
Unopened: 2 years.
Use within 28 days of first opening.

6.4 Special precautions for storage
Store below 25° C

6.5 Nature and contents of container
Low density polyethylene dropper bottles (with LDPE dropper tips) containing 3 ml, 5 ml or 10 ml of solution. The drop size is 35 microlitres. Each bottle has a medium impact polystyrene (MIPS) screw-cap.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling
No special requirements.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. Manufactured In India By:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com

Ketorolac Tromethamine Opthalmic Solution USP 0.5% w/v Taj Pharma

Package leaflet: Information for the patient

Ketorolac Tromethamine Opthalmic Solution USP 0.5% w/v Taj Pharma.

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.
– Keep this leaflet. You may need to read it again.
 – If you have any further questions, ask your doctor or pharmacist.
– This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
– If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor.

What is in this leaflet
1. What  Ketorolac is and what it is used for
2. Before you are given Ketorolac
3. How you will be given  Ketorolac
4. Possible side effects
5. How Ketorolac is stored
6. Further Information

1. What Ketorolac is and what it is used for
Ketorolac is used to prevent and relieve eye inflammation following surgery on the eye in adults.
Ketorolac belongs to a group of medicines known as non-steroidal anti-inflammatory drugs (NSAIDs). The active ingredient in Ketorolac is Ketorolac.

2. Before you are given Ketorolac
Do not use Ketorolac

  • If you are allergicto Ketorolac, or any of the other ingredients of this medicine (listed in section 6).
  • If you are allergic to aspirin or any other similar drugs.

Warnings and precautions
Talk to your doctor or pharmacist or nurse before using Ketorolac.
If you suffer from, or have in the past suffered from:

  • viral or bacterial infections of the eye
  • bleeding tendencies (for example, anaemia) or stomach ulcers
  • diabetes
  • rheumatoid arthritis
  • dry eye syndrome
  • asthma after using non-steroidal anti-inflammatories
  • or if you have had recent eye surgery.

Children
Ketorolac should not be prescribed for use in children

Other medicines and Ketorolac
Tell your doctor or pharmacist if you are using, have recently used or might use any other medicine.

If you use Ketorolac with another eye medicine, leave at least 5 minutes between putting in Ketorolac and the other medicine.

Pregnancy and breast-feeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

Ketorolac should not be used if you are pregnant or are breast-feeding, unless your doctor recommends it.

Driving and using machines
Ketorolac may cause temporary blurred vision. Do not drive or use machinery until the symptoms have cleared.

Ketorolac contains benzalkonium chloride
This medicine contains 0.1 mg benzalkonium chloride in each milliliter which is equivalent to 0.1 mg/ml.

Benzalkonium chloride may be absorbed by soft contact lenses and may change the colour of the contact lenses. You should remove contact lenses before using this medicine and put them back 15 minutes afterwards.

Benzalkonium chloride may also cause eye irritation, especially if you have dry eyes or disorders of the cornea (the clear layer at the front of the eye). If you feel abnormal eye sensation, stinging or pain in the eye after using this medicine, talk to your doctor.

3. How you will be given Ketorolac
Always use this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure. The recommended doseis 1 drop into the affected eye(s), 3 times a day, starting 24 hours before surgery and continuing for up to 3 weeks after eye surgery.

Instructions for use

  • You must not use the bottle if the tamper-proof seal on the bottle neck is broken before you first use it. Apply your eye drops in the following way:
  1. Wash your hands. Tilt your head back and look at the ceiling.
    2. Gently pull the lower eyelid down until there is a small pocket.
    3. Turn the bottle upside down and squeeze it to release one drop into each eye that needs treatment.
    4. Let go of the lower lid, and close your eye for 30 seconds.

If a drop misses your eye, try again.

To avoid contamination or injury, do not let the tip of the dropper touch your eye or anything else.

Replace and tighten the cap straight after use.

Wipe off any excess liquid from your cheek with a clean tissue.

The proper application of your eye drops is very important. If you have any questions ask your doctor or pharmacist.

If you use more Ketorolac than you should
The application of too many drops is unlikely to lead to unwanted side effects. Apply your next dose at the normal time. If, by accident, anyone drinks this medicine, drink fluids to dilute and contact your doctor.

If you forget to use Ketorolac
If you forget a dose apply it as soon as you remember, unless it is almost time for your next dose, in which case you should miss out the forgotten dose. Then take your next dose as usual and continue with your normal routine.

Do not take a double dose to make up for a forgotten dose.

If you stop using Ketorolac
Ketorolac should be used as advised by your doctor. If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible Side Effects
Like all medicines, this medicine can cause side effects, although not everybody gets them.

Side effects related to the cornea (the surface of the eye) may be more likely if Ketorolac is used for longer than two weeks or if you are using topical steroid drops at the same time or if you have a related eye condition. You should see your doctor immediately if you experience pain, increased irritation in the eye or changes in vision.

Very common may affect more than 1 in 10 people
Irritation of the eye, stinging and/or burning in the eye, eye pain.

Common may affect up to 1 in 10 people
Allergic reaction, eye and/or eyelid swelling/puffiness, itchy eyes, red eye, infection of the eye, inflammation of the eye (surface or inside), bleeding of the retina, swelling of central retina (light-sensitive layer of the eye), headache, accidental injury caused by the tip of the dropper touching the eye, increased pressure in the eye, blurred and/or diminished vision.

Uncommon may affect up to 1 in 100 people
Inflammation or damage to the front clear layer of the eye, eye dryness and/or watery eyes.

Not known frequency cannot be estimated from the available data.
Damage on the surface of the eye such as thinning, erosion, degradation of cell(s), difficulty in breathing or wheezing, aggravation of asthma, ulcer-damage to the surface of the eye.

Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.

5. How Ketorolac is stored
Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the bottle label and the bottom of the carton after EXP. The expiry date refers to the last day of that month.
Throw the bottle away 28 days after opening, even if there is solution remaining.
Store below 25°C.
Do not use this medicine if you notice the tamper-proof seal is broken.
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6. Further information

What Ketorolac contains
The active substance is Ketorolac Tromethamine.
Each ml contains:
Active: Ketorolac Tromethamine USP 0.5%w/v
Preservative: Benzalkonium chloride 0.01%
The other ingredients are benzalkonium chloride, disodium edetate, octoxinol 40, sodium chloride, sodium hydroxide or hydrochloric acid (to adjust pH) and purified water.

What Ketorolac looks like and contents of the pack
Ketorolac is a clear, colourless to slightly yellow solution in a plastic bottle.
Each pack contains 1 plastic bottle with a screw cap. Each bottle is about half full and contains 3 ml, 5 ml or 10 ml of the eye drops as written on the front of the pack. Not all pack sizes may be marketed.

7. Manufactured In India By:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com